To the Editor: During the 17 years since the Surgeon General's
first report on smoking, intense research activity has been focused
on the carcinogenic potential of the tar component of cigarette
smoke. Only one definite chemical carcinogen -- benzopyrene --
has been found. Conspicuous because of its absence is research into
the role of the radioactive component of cigarette smoke.

The alpha emitters polonium-210 and lead-210 are highly concentrated
on tobacco trichomes and insoluble particles in cigarette
smoke (1). The major source of the polonium is phosphate fertilizer,
which is used in growing tobacco. The trichomes of the leaves concentrate
the polonium, which persists when tobacco is dried and processed.

Levels of Po-210 were measured in cigarette smoke by Radford and
Hunt (2) and in the bronchial epithelium of smokers and nonsmokers
by Little et al. (3) After inhalation, ciliary action causes the insoluble
radioactive particles to accumulate at the bifurcation of segmental
bronchi, a common site of origin of bronchogenic carcinomas.

In a person smoking 1 1/2 packs of cigarettes per day, the radiation
dose to the bronchial epithelium in areas of bifurcation is 8000
mrem per year -- the equivalent of the dose to the skin from 300
x-ray films of the chest per year. This figure is comparable to total-body
exposure to natural background radiation containing 80
mrem per year in someone living in the Boston area.

It is a common practive to assume that the exposure received
from a radiation source is distributed throughout a tissue. In this
way, a high level of exposure in a localized region -- e.g. bronchial
epithelium -- is averaged out over the entire tissue mass, suggesting
a low level of exposure. However, alpha particles have a range of
only 40 um in the body. A cell nucleus of 5 to 6 um that is traversed
by a single alpha particle receives a dose of 1000 rems. Thus, although
the total tissue dose might be considered negligible, cells
close to an alpha source receive high doses. The Po-210 alpha activity
of cigarette smoke may be a very effective carcinogen if a multiple
mutation mechanism is involved.

Radford and Hunt have determined that 75 per cent of the alpha
activity of cigarette smoke enters the ambient air and is unabsorbed
by the smoker, (2) making it available for deposit in the lungs
of others. Little et al. have measured levels of Po-210 in the lungs of
nonsmokers that may not be accounted for on the basis of natural
exposure to this isotope.

The detrimental effects of tobacco smoke have been considerably
underestimated, making it less likely that chemical carcinogens
alone are responsible for the observed incidence of tobacco-related
carcinoma. Alpha emitters in cigarette smoke result in appreciable
radiation exposure to the bronchial epithelium of smokers and
probably secondhand smokers. Alpha radiation is a possible etio-
logic factor in tobacco-related carcinoma, and it deserves further
study.

To the Editor: In a letter in the Feb 11 issue, Winters and DiFranza (1)
correctly point out that alpha radiation from polonium-210 is a possible
causal factor in tobacco-related carcinoma, but they incorrectly state that
"inhaled" Po210 is a factor and that research on this important possibility
has been neglected. I will briefly review recent pertinent research.

Radford and Hunt (2) first suggested that alpha radiation from Po210 in
cigarette smoke may be important in the genesis of bronchial cancer.
Little et al. (3) found surprisingly high concentrations of Po210 at single
bronchial bifurcations in seven of 37 cigarette smokers. Holtzman and
others (4 - 6) raised doubts about the validity of these observations
because inhaled volatile Po210 is soluble and rapidly cleared.
Subsequently, I determined (7) that lead-210 (a beta-emitting precursor of
Po210) is highly concentrated in tobacco trichomes and that trichome
combustion in burning cigarettes produces insoluble, Pb210-enriched
particles in mainstream smoke. Thus, the high concentrations of Po210
observed at segmental bifurcations (4 - 6) can be explained by the
persistence of insoluble, Pb210-enriched particles deposited at
bifurcations and by the ingrowth of Po210 in these particles. (7,8)
Radford and Martell (9) confirmed that the excess Po210 in the bronchial
epithelium of smokers is accomplished by a larger excess of Pb210.

Fleischer and Parungo (10) provided experimental evidence indicating that
radon decay products and Pb210 are concentrated on trichome tips.
Mechanisms of accumulation of Pb210 on tobacco trichomes are discussed by
Martell and Poet. (11)

Two recent studies (12,13) indicate that alpha radiation from inhaled
indoor radon progeny may explain the incidence of lung cancer in
nonsmokers. Martell and Sweder (14) report that indoor radon decay
products that pass from the room air through burning cigarettes into
mainstream smoke are present in large, insoluble smoke particles that are
selectively deposited at bifurcations. Thus, the smoker receives alpha
radiation at bronchial bifurcations from these three sources: from indoor
radon progeny inhaled between cigarettes, from Po214 in mainstream smoke
particles, and from Po210 that grows into Pb210 enriched particles that
persist at bifurcations. I estimate that the cumulative alpha dose
at the bifurcations of smokers who die of lung cancer is about 80rad
(1600rem) -- a dose sufficient to induce malignant transformations by alpha
interactions with basal cells.

Edward A Martell, Ph.D.
National Center for Atmospheric Research
Boulder, CO 80307

Martell EA, Sweder KS. The roles of polonium isotopes in the etiology
of lung cancer in cigarette smokers and uranium miners. In: Gomez M,
ed. Proceedings of a symposium on radiation hazards in mining.
New York: American Institute of Mining Engineers, 1982:383-389.

To the Editor: The presence of Po210 and Pb210 in cigarette smoke may
help to explain a paradox found in smokers of low-tar, low-nicotine
cigarettes.

Hammond et al. (1) noted that the number of deaths from lung cancer was
greater in subjects who smoked 20 to 39 low-tar, low-nicotine cigarettes
a day than in those who smoked one to 19 high-tar, high-nicotine
cigarettes a day. Thus, the number of cigarettes smoked may be more
important than their tar and nicotine content.

Two features of low-tar low-nicotine cigarettes that help to reduce
the amounts of tar in inhaled smoke may have little effect or adverse
effects on the amounts of Po210 and Pb210 in inhaled smoke. In the
first place, the use of higher porosity paper and perforated filters may
enhance the completeness of combustion. Although this may decrease the
tar and nicotine content in inhaled smoke, it may increase the pyrolysis
of trichomes, resulting in smoke particles with higher specific activities
of Pb210. Secondly, cigarette filters have been shown to have no
noticeable protective effect against Po210 inhalation. (2) If Po210
and Pb210 contribute to tobacco related cancer, then the number of
cigarettes smoked may be more important than the tar or nicotine content.

Although intensive effort has been successful in producing low-tar,
low-nicotine cigarettes, perhaps future research should be aimed toward
the development of low Po210, low Pb210 cigarettes.

To the Editor: Contrary to the contention of Winters and DiFranza that
research into the carcinogenic potential of the radioactive component of
cigarette smoke is conspicuous by its absence, we and others have studied
and reported on this risk since the theory was first proposed by Radford
and Hunt in 1964. (1) Within five years of the initial report that the
radioactive alpha emitter Po210 was present in mainstream smoke and in
samples of bronchial epithelium from cigarette smokers, results from over
two dozen related studies were published. The source of the Po210 and
Pb210 (The beta emitter Pb210 is the long lived precursor that supports the
Po210) was investigated, (2) the contents of these nuclides in various
tobaccos documented, (3) the fraction transferred to the mainstream or
sidestream smoke (or both) determined, (4) and the concentration in the
whole lungs of smokers and nonsmokers measured. (5)

Measurements made with cigarette smoke condensate demonstrate that although
radium and thorium are also present in cigarette smoke, 99% of the alpha
activity is from Po210. (6) Measurements of the whole lungs of smokers and
exsmokers show that the inhaled Po210 is retained in the lower lung. (7)

A relatively new detection technique using nuclear-track-etch film has
allowed us to determine the amount and microdistribution of alpha activity
on the bronchial mucosa in fresh autopsy specemins. (8) We examined about
one-fourth of the upper respiratory tract in each of seven persons (Three
smokers, two exsmokers, and two nonsmokers). A few areas of slightly
elevated alpha activity were found in each of the bronchial trees examined
except that of one young smoker, in which efficient bronchial clearance
would be expected. The average dose rate to the basal cells of the
bronchial epithelium from alpha activity in these seven persons ranged from
2.0 to 40mrem per year. For comparison, the natural background dose from
inhaled radon-daughter alpha activity is about 2000mrem per year. One area
of a few square millimeters, containing markedly elevated activity, was
found in the bronchii of an older smoker. This area could deliver an
annual dose of about 20,000mrem, comparable to the results originally
reported by Bradford and Hunt. This activity can lead to a lifetime dose
similar to the alpha dose that appears to yield an elevated risk of lung
cancer in underground miners. However, the total dose cannot be
calculated, since the residence time of such an alpha emitting spot on the
bronchial tree is not known.

The importance of proper assessment of the risk to cigarette smokers
from radionuclides in the smoke cannot be overstated. In view of the
present knowledge, it is improbable that a single area of a few square
millimeters of high alpha activity in the bronchial tree is important.
Nonetheless, Po210 is the only component in cigarette smoke tar that has
produced cancers by itself in laboratory animals as a result of inhalation
exposure. (9)

We firmly believe that the role of alpha radiation in tobacco related
carcinogenesis deserves further study. The techniques to define its role
in this disease are now available.

Beverly S. Cohen, Ph.D.
Naomi H. Harley, Ph.D.
New York University School of Medicine
New York, NY 10016

To the Editor: The letter of Winters and DiFranza has renewed the earlier
suggestion that the radioisotope Po210 may have an important role in the
induction of lung cancer in smokers. In particular, it is claimed that
the radionuclide may be deposited very inhomogeneously in the bronchial
epithelium, in the form of a limited number of relatively "hot" particles,
and that such hot particles may be much more effective carcinogenically
than the same amount of radioactivity would be if it were more uniformly
distributed. The basis of both these claims must be questioned.

Evidence on the question of the carcinogenicity of hot particles has
been reviewed by the International Commission on Radiological Protection,
(1) which found the actual situation to be just the reverse of that
suggested by the correspondents. The evidence cited for the actual
formation of hot particles (2) comes from a study of the Po210 in a series
of several very small samples of bronchial epithelium (usually less than
25mg) collected from smokers' lungs. In these measurements, the activities
in individual samples were so low that for a proportion at least, only
about 20 counts were recorded in a counting period of three to seven days
against a background of 40 counts. Proper analysis of the statistical
validity of these observations was not given by the original authors and is
not possible from their reported data. Contrary evidence, not cited by the
correspondents, is provided by a somewhat earlier paper (3) that reported
the results of auto radiographic examination of excised segments of
bronchial epithelium; this study found no evidence of surface concentrations
of alpha activity of more than 0.01pCi per square centimeter, corresponding
to a mean dose rate of about 10mrem per year. Finally, the correspondents'
suggestion that the "major source of the polonium is phosphate fertilizer"
is not substantiated and is at variance with published data (3,4) indicating
that it originates as atmospheric fallout of the decay products of natural
radon-222.

To the Editor: The Surgeon General's recent denunciation of tobacco
smoking and the American Cancer Society's pessimistic prognosis that
lung cancer will be the number one cause of death from cancer in women
by 1985 (1) provide timely emphasis on the recent NEJM letter on radioactive
alpha emitters in tobacco smoke. Some of the further study encouraged by
Winters and DiFranza has in fact been performed, yielding results far more
foreboding than expected.

In two separate studies, Little et al. (2,3) have induced respiratory
tumors in hamsters by intratracheal instillation of Po210 in various
amounts down to less than one-fifth that inhaled by a heavy cigarette
smoker (one who consumes two packs a day) during 25 years. The incidence
of tumors at the lowest dose was 13%, including borderline carcinomas, and
was 11% for frankly malignant tumors.

Contrary to the expected results of most radiobiologists, dose reduction
did not result in either a constant dose-response ratio (the linear response
hypothesis) or a larger dose-response ratio (The threshold or sigmoid
hypothesis) but instead produced a marked decrease in the dose-response
ratio. In one study, a reduction in activity from 0.700microCi of Po210
instilled to 0.00375microCi of Po210 instilled -- about a two hundred-fold
decrease -- resulted in a decrease in the incidence of tumors from 61% to
13% (including borderline cases) -- only a fourfold decrease.

This decrease in the dose-response ratio with decreasing dose has also
been observed in other studies of the effects of low dose alpha radiation
and other radiation particles with high linear energy transfer (LET). In
a study of osteosarcoma induction by alpha radiation, Muller et al. (4)
had over a 100-fold decrease in the dose-response ratio from their highest
dose (1500rad) to their lowest dose (15rad). For neutron radiation, Rossi
et al. (5) found similar results, with leukemia induction having the
smallest dose-response ratio in the lowest dose in survivors of the atomic
bomb. Similarly, Hall et al. (6) found that both dose protraction and dose
reduction for neutron radiation increased the cell-lethality-dose ratio
of hamster cells in vitro.

The importance of these results with low dose irradiation by high LET
particles should not be overlooked. Doses in the range of several thousand
to 10^5 rad have generally been necessary for the experimental induction
of lung cancer by beta or gamma radiation (with low LET), (7,8) as compared
with the studies by Little et al., in which the lowest dose of 15rad
(0.00375microCi in the lung volume for the lifetime of the hamsters) induced
cancer at an incidence of about 13%.

Presumably, the high density of ionization along the track of alpha
radiation (about one ion pair for every 2 Angstrom traveled) and other
high-LET radiation is the prime factor causing Po210 to be an extremely
efficient carcinogen.

Clearly, further work is warranted in this area, but we should not hesitate
to disseminate the information already at hand -- that the alpha-radiation
exposure to the lungs of tobacco smokers is extremely important.

To the editor: The letter by Winters and DiFranza rivets much needed
attention on the earlier finding of Radford and Hunt, (1) which is crucial
to an understanding of the pathogenesis of smoking diseases. (2,3)

Although Winters and DiFranza tellingly describe the mechanisms by which
Po210 on insoluble particles in cigarette smoke causes lung cancer, they
neglect the even more important matter of how Po210 and other mutagens
from tobacco smoke cause malignant neoplasms, degenerative cardiovascular
diseases, and other diseases throughout the body of smokers (Table 1).

TABLE 1.

Effects of Smoking on Tissues Directly and Indirectly
Exposed to Radiation in Current Cigarette Smokers*

Cause of Death

Number of Deaths

Observed/Expected (ratio)

Observed

Expected

All causes

36,143

20,857

1.73

Emphysema

1,201

81

14.83

Cancer:

Of directly exposed tissue

3,061

296

10.34

-

Of buccal cavity

110

26

4.23

-

Of pharynx

92

7

13.14

-

Of larynx

94

8

11.75

-

Of lung and bronchus

2,609

231

11.29

-

Of esophagus

156

24

6.50

Of indirectly exposed tissue

4,547

3,292

1.38

-

Of stomach

390

257

1.52

-

Of intestines

662

597

1.11

-

Of rectum

239

215

1.11

-

Of liver and biliary passages

176

75

2.35

-

Of pancreas

459

256

1.79

-

Of prostate

660

504

1.31

-

Of kidney

175

124

1.41

-

Of bladder

326

151

2.16

-

Of brain

160

152

1.05

-

Malignant lymphomas

370

347

1.07

-

Leukemias

333

207

1.61

-

All other cancers

597

407

1.47

All cardiovascular diseases

21,413

13,572

1.58

-

Coronary heart disease

13,845

8,787

1.58

-

Aortic aneurysm

900

172

5.23

-

Cor pulmonale

44

8

5.50

-

All other cardiovascular

6,624

4,605

1.44

Ulcer of stomach, duodenum or jejenum

289

93

3.10

Cirrhosis of liver

404

150

2.69

*Data adapted from Rogot and Murray. (4)

Volatilized, soluble Po210, produced at the burning temperature of
cigarettes, (1) is cleared from the bronchial mucosa at the expense of
the rest of the body, being absorbed through the pulmonary circulation
and carried by the systemic circulation to every tissue and cell, causing
mutations of cellular genetic structures, deviation of cellular
characteristics from their optimal normal state, accelerated aging, and
early death from a body-wide spectrum of diseases, reminiscent of the
disease and mortality patterns afflicting early radiologists and others
with long-term exposure to x-rays and other forms of ionizing radiation.
(5,6)

The proof of circulating mutagens from smoking is that Po210 and other
mutagens can be recovered not only from tobacco smoke and bronchial mucosa,
but also from the blood and urine of smokers. (1,7)

Rogot E., Murray JL. Smoking and causes of death among U.S. veterans:
16 years of observation. Public Health Rep. 1980:213-222

Warren S. Longevity and causes of death from irradiation in physicians.
JAMA. 1956; 162:464-468

National Academy of Sciences-National Research Council. Long term
effects of ionizing radiation from external sources. Washington
D.C.: National Research Council, 1961.

Office on Smoking and Health. Smoking and Health: a report of the
Surgeon General. Rockville, MD: Office on smoking and health, 1979.
(DHEW publication no. [PHS]79-50066).

To the editor: We concur with Drs. Winters and DiFranza that the scientific
and medical community as well as public health officials should be more
concerned with the detrimental effects of cigarette smoking. Reviews on the
carcinogenic effect of cigarette smoke are made available to United States
physicians at regular intervals through the Surgeon General's reports
entitled Smoking and Health. (1) From these reports it is clear that
benzo(a)pyrene is by far not the only carcinogen identified in cigarette
smoke. Benzo(a)pyrene serves merely as an indicator for the wide
spectrum of carcinogenic polycyclic hydrocarbons, all of which are
pyro synthesized by the same mechanism during smoking. Aside from these
hydrocarbons, cigarette smoke contains other carcinogens such as aza-arenes,
aromatic amines (including beta-napthylamine), nickel, volatile nitrosamines,
and especially tobacco-specific N-nitrosamines. (1-3) The N-nitrsamine
compounds are formed by nitrosation of nicotine and other alkaloids; their
concentrations in tobacco and smoke exceed those of nitrosamines found in
other consumer products by at least several hundred fold. These nitrosamines
are probably formed from nicotine in vivo. (2,3) Above all, one needs to
consider that the carcinogenic potential of tobacco is a composite effect
of tumor initiators, tumor promoters, or co-carcinogens, and organ-specific
carcinogens. (1,2)

To the editor: We thank Dr. Martell and Drs. Cohen and Harley for their
reviews of the literature. Judging by the response to our original letter,
research into the radioactive component has been in progress since the
early 1960's, but the existence of this research is largely unknown outside
a small segment of the scientific community. We were gratified to receive
hundreds of phone calls from smokers who quit on learning about the alpha
radiation in cigarette smoke.

Hill examined the lungs of only two smokers old enough to have metaplastic
lesions. In addition, he analyzed whole bronchial specemins weighing 5g to
15g, of which only 2% by weight was epithelium. His result of 0.007 pCi
per gram of tissue is in reasonable agreement with Little's result of
0.012pCi per gram of whole bronchus and thus does not disprove the
existence of hot spots. In addition, the accumulation of Pb210 on tobacco
leaves is from natural and unnatural radon-222 decay products and from
phosphate fertilizers.

We thank Dr. Wagner for pointing out that alpha radiation now appears to
be 1000 times more carcinogenic than gamma radiation. Standard practice
reguards alpha radiation as only 10 to 20 times as carcinogenic as gamma
radiation.

The growing list of malignant diseases associated with smoking, presented
by Dr. Ravenholt, begs for causal explanation. Smokers have higher levels
of Po210 in the lungs, bone blood and urine. (1-3) Higher levels of Po210
have been consistently found in smokers in the liver, kidney, spleen,
pancreas, and gonads. (4,5) A study with an adequate number of subjects
would probably demonstrate a significant difference. The Po210 must be
strongly considered as a cause of these cancers.

Drs. Cohen and Harley report finding one "hot spot" on studying the
alpha activity of alpha Po210 in tracheal autopsy specemins of seven people,
three of whom were smokers. (6) This supports Little and his colleagues'
previous findings of :hot spots" in 7 out of 37 smokers.

We thank Drs. Hoffmann and Wynder for correcting us about the variety
of chemical carcinogens present in cigarette smoke. It is possible that
chemicals and Po210 act as cocarcinogens in the following manner. Chemical
and possibly physical agents create metaplastic nonciliated epithilial
lesions. Auerbach demonstrated such lesions in 100% of heavy smokers. (7)
The Po210 present on insoluble particles gains entrance to epithelial cells
in such non-ciliated areas of mucous stagnation. Ingrowth of Po210 from the
decay of Pb210 results in high doses of alpha radiation to already
metaplastic cells. (8) Continued smoking ensures a steady delivery of
Pb210 to these stagnant sites. Little and his co-workers have demonstrated
synergism between benzo(a)pyrene and Po210 in an animal model. (9)

In view of the potential role of alpha radiation in a variety of tobacco
related neoplasias, we believe that this area deserves more intense
research. We find it surprising that the National Cancer Institute, with
an annual budget of $500 million, has no active grants on alpha radiation
as a cause of lung cancer (National Cancer Institute: personal
communication).

We have found when educating smokers that more are encouraged to quit
as they learn of the presence of radiation in cigarette smoke.